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Public Release Summary
on the evaluation of the new active zilpaterol hydrochloride in the product Zilmax Medicated Premix
APVMA product number 67405
May 2020
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© Australian Pesticides and Veterinary Medicines Authority 2020
ISSN 1443-1335 (electronic)
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CONTENTS iii
CONTENTS
PREFACE 1
About this document 1
Making a submission 1
Further information 2
1 INTRODUCTION 3
1.1 Applicant 3
1.2 Purpose of application 3
1.3 Proposed claims and use pattern 3
1.4 Mode of action 3
1.5 Overseas registrations 3
2 CHEMISTRY AND MANUFACTURE 4
2.1 Active constituent 4
2.2 Formulated product 5
2.3 Recommendations 6
3 TOXICOLOGICAL ASSESSMENT 7
3.1 Evaluation of toxicology 7
3.2 Health-based guidance values and poisons scheduling 10
3.3 Recommendations 11
4 RESIDUES ASSESSMENT 12
4.1 Metabolism 12
4.2 Analytical methods 12
4.3 Residue definition 13
4.4 Residues in food and animal feeds 13
4.5 Estimated dietary intake 14
4.6 Recommended Maximum Residue Limits 15
5 ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD 16
5.1 Commodities exported 16
5.2 Destination and value of exports 16
5.3 Comparison of Australian MRLs with Codex and international MRLs 16
5.4 Potential risk to trade 18
6 WORK HEALTH AND SAFETY ASSESSMENT 20
6.1 Health hazards 20
6.2 Occupational exposure 20
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iv PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
6.3 Public exposure 20
6.4 Recommendations 20
7 ENVIRONMENTAL ASSESSMENT 22
7.1 Fate and behaviour in the environment 22
7.2 Recommendations 22
8 EFFICACY AND SAFETY ASSESSMENT 23
8.1 Proposed product use pattern 23
8.2 Efficacy and target animal safety 23
8.3 Recommendations 24
9 PROPOSED ZILPATEROL TRADE MANAGEMENT PLAN 26
9.1 Zilpaterol Management Plan 26
10 LABELLING REQUIREMENTS 29
ABBREVIATIONS 34
GLOSSARY 37
REFERENCES 38
LIST OF TABLES Table 1: Nomenclature and structural formula of the active constituent zilpaterol hydrochloride 4
Table 2: Key physicochemical properties of the active constituent zilpaterol hydrochloride 5
Table 3: Key aspects of the formulated product Zilmax Medicated Premix 6
Table 4: Physicochemical properties of the product Zilmax Medicated Premix 6
Table 5: Amendments to the APVMA MRL Standard 15
Table 6: Proposed Australian and current international MRLs for zilpaterol 17
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PREFACE 1
PREFACE
The Australian Pesticides and Veterinary Medicines Authority (APVMA) is the Australian Government
regulator responsible for assessing and approving agricultural and veterinary chemical products prior to their
sale and use in Australia. Before approving an active constituent and/or registering a product, the APVMA
must be satisfied that the statutory criteria, including the safety, efficacy, trade and labelling criteria, have
been met. The information and technical data required by the APVMA to assess the statutory criteria of new
chemical products, and the methods of assessment, must be consistent with accepted scientific principles
and processes. Details are outlined on the APVMA website.
The APVMA has a policy of encouraging transparency in its activities and seeking community involvement in
decision making. Part of that process is the publication of public release summaries for products containing
new active constituents. This Public Release Summary is intended as a brief overview of the assessment
that has been conducted by the APVMA and of the specialist advice received from advisory agencies,
including other Australian Government agencies and State departments of primary industries. It has been
deliberately presented in a manner that is likely to be informative to the widest possible audience to
encourage public comment.
About this document
This Public Release Summary indicates that the APVMA is considering an application for registration of an
agricultural or veterinary chemical. It provides a summary of the APVMA’s assessment, which may include
details of:
the toxicology of both the active constituent and product
the residues and trade assessment
occupational exposure aspects
environmental fate, toxicity, potential exposure and hazard
efficacy and target crop or animal safety.
Comment is sought from interested stakeholders on the information contained within this document.
Making a submission
In accordance with sections 12 and 13 of the Agvet Code, the APVMA invites any person to submit a
relevant written submission as to whether the application for approval of the active constituent zilpaterol
hydrochloride and registration of the product Zilmax Medicated Premix should be granted. Submissions
should relate only to matters that the APVMA is required, by legislation, to take into account in deciding
whether to grant the application. These matters include aspects of public health, occupational health and
safety, chemistry and manufacture, residues in food, environmental safety, trade, and efficacy and target
animal safety. Submissions should state the grounds on which they are based. Comments received that
address issues outside the relevant matters cannot be considered by the APVMA.
https://apvma.gov.au/
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2 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Submissions must be received by the APVMA by close of business on 16 June 2020 and be directed to the
contact listed below. All submissions to the APVMA will be acknowledged in writing via email or by post
Relevant comments will be taken into account by the APVMA in deciding whether the product should be
registered and in determining appropriate conditions of registration and product labelling.
When making a submission please include:
contact name
company or group name (if relevant)
email or postal address (if available)
the date you made the submission.
All personal information, and confidential information judged by the APVMA to be confidential commercial
information (CCI)1 contained in submissions will be treated confidentially. Unless requested by the submitter,
the APVMA may release a submission, with any CCI redacted, to the applicant for comment.
Written submissions on the APVMA’s proposal to grant the application for registration that relate to the
grounds for registration should be addressed in writing to:
Case Management and Administration Unit
Australian Pesticides and Veterinary Medicines Authority
GPO Box 3262
Sydney NSW 2001
Phone: +61 2 6770 2300
Email: [email protected].
Further information
Further information can be obtained via the contact details provided above.
Copies of technical evaluation reports covering chemistry, efficacy and safety, toxicology, occupational
health and safety aspects, residues in food and environmental aspects are available from the APVMA on
request.
Further information on public release summaries can be found on the APVMA website.
1 A full definition of "confidential commercial information" is contained in the Agvet Code.
mailto:[email protected]://apvma.gov.au/
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INTRODUCTION 3
1 INTRODUCTION
This publication provides a summary of the data reviewed and an outline of the regulatory considerations for
the proposed approval of the new active constituent, zilpaterol hydrochloride and registration of the product
Zilmax Medicated Premix.
1.1 Applicant
Intervet Australia Pty Ltd.
1.2 Purpose of application
Intervet Australia Pty Ltd has applied to the APVMA for registration of the new product Zilmax Medicated
Premix, as an oral medicated premix formulation containing 48 g/kg of the new active constituent zilpaterol
hydrochloride.
1.3 Proposed claims and use pattern
Zilmax Medicated Premix is indicated for increased carcass leanness, increased dressing percent, improved
rate of body weight gain and improved feed efficiency in cattle fed in confinement for slaughter during the
last 20 days on feed. Zilmax Medicated Premix will be administered to manufactured feeds at 8.3 g zilpaterol
hydrochloride per tonne (8.3 mg/kg in the feed) on a 100 per cent dry matter basis to derive a daily dose of
43–128 mg, depending on body weight and consumption rates. Zilmax Medicated Premix can also be added
to liquid feeds intended for addition to dry feeds and consumed at the same daily dose of 43–128 mg,
depending on body weight and consumption rates.
1.4 Mode of action
Zilpaterol is a beta II- adrenergic receptor agonist. It improves growth rate, increases skeletal muscle content
and reduces body fat content. Beta II- adrenergic agonists enhance animal growth by binding to beta II-
adrenergic receptors on skeletal muscle cells and adipocytes. When bound to receptors, the biochemical
processes of tissue growth are modified by increasing lipolysis, decreasing lipogenesis, decreasing protein
degradation, and increasing protein synthesis.
1.5 Overseas registrations
The product is currently registered in the USA and Canada as Zilmax® (48 g/kg zilpaterol hydrochloride), for
increased rate of weight gain, improved feed efficiency, and increased carcass leanness in cattle fed in
confinement for slaughter during the last 20 to 40 days on feed. It is also registered in Brazil, Colombia,
Costa Rica, Dominican Republic, Guatemala, Honduras, Kazakhstan, Mexico, Nicaragua, Panama, Peru,
South Africa and South Korea.
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4 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
2 CHEMISTRY AND MANUFACTURE
2.1 Active constituent
The active constituent zilpaterol hydrochloride is a beta II- adrenergic agonist intended for use as a
medicated premix for administration to cattle fed in confinement for slaughter. Zilpaterol hydrochloride is not
described in any pharmacopeia monographs. Details of the chemical name, structure, and physicochemical
properties of zilpaterol hydrochloride are listed below (Tables 1–2).
Table 1: Nomenclature and structural formula of the active constituent zilpaterol hydrochloride
Common name (ISO): Zilpaterol hydrochloride
IUPAC name: IUPAC: (6RS,7RS)-7-Hydroxy-6-(isopropylamino)-4,5,6,7-tetrahydro-
imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one hydrochloride (1:1)
Chemical Abstracts: Trans-(±)-4,5,6,7-tetrahydro-7-hydroxy-6-[(1-
methylethyl)amino]-imidazo[4,5,1-jk][1]benzazepin-
2(1H)-one, monohydrochloride
CAS registry number: 119520-06-8
Molecular formula: C14H19N3O2.HCl
Molecular weight: 297.78
Structural formula:
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CHEMISTRY AND MANUFACTURE 5
Table 2: Key physicochemical properties of the active constituent zilpaterol hydrochloride
Physical form: A white to slightly yellow anhydrous powder
Melting point: >200°C
Solubility in water: Soluble in water: 150 g/l
Organic solvent solubility: Slightly soluble in methanol
Insoluble in chloroform, ethanol, acetone and toluene
Dissociation constant (PKa): pKa 8.09 at 26°C
Octanol/water partition
coefficient (Log Kow/KOW):
Log Kow < 1 at pH 5,7,9 and at 25oC
Vapour pressure: 8 × 10-6 Pa at 25°C
Particle size distribution: NMT 5% for fraction less than or equal to 15 µm,
NMT 10% for fraction not smaller than 200 µm,
NMT 0.5% for fraction not smaller than 300 µm
The chemistry aspects of zilpaterol hydrochloride active constituent (manufacturing process, quality control
procedures, batch analysis results and analytical methods) have been considered and found to be acceptable.
2.2 Formulated product
Zilmax Medicated Premix is a granular formulation that will be administered in feed. The product will be
formulated overseas, and packaged in 10 kg multiwall bags (three outer paper layers with an inner layer of
low density polyethylene (LDPE) in direct contact with the product). Suitable details of the product
formulation, specifications for the ingredients, formulation process and quality control, product specifications,
stability data, analytical methods for the active constituent in the product, and details of the packaging were
evaluated.
Tables 3 and 4 outline some key aspects of the formulation and physicochemical properties of the product.
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6 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Table 3: Key aspects of the formulated product Zilmax Medicated Premix
Distinguishing name: Zilmax Medicated Premix
Formulation type: Feed premix (granular)
Active constituent
concentration/s:
Zilpaterol hydrochloride (48 g/kg)
Table 4: Physicochemical properties of the product Zilmax Medicated Premix
Physical form: Cream to brown grains
Particle size: Not less than 99% of the product passes through a 2 mm sieve
Not more than 2% retention on a 0.5 mm sieve
Storage stability: To be stored below 30°C (room temperature)
2.3 Recommendations
The APVMA has evaluated the chemistry of the active constituent zilpaterol hydrochloride and associated
product Zilmax Medicated Premix, including the manufacturing process, quality control procedures, stability,
batch analysis results and analytical methods, and found them to be acceptable.
Based on a review of the chemistry and manufacturing details, approval of the active constituent zilpaterol
hydrochloride and registration of the product Zilmax Medicated Premix, are supported from a chemistry
perspective.
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TOXICOLOGICAL ASSESSMENT 7
3 TOXICOLOGICAL ASSESSMENT
The APVMA has considered the toxicological profile and likely exposure associated with the use of the
formulated product Zilmax Medicated Premix and the active constituent zilpaterol hydrochloride.
3.1 Evaluation of toxicology
The toxicological data submitted on the active constituent, zilpaterol hydrochloride, is considered sufficient to
characterise its toxicity and to establish applicable health-based guidance values for the purposes of
determining the dietary risk posed by the presence of the residues in treated livestock.
Chemical class and mode of activity
Zilpaterol hydrochloride is a beta II- adrenergic agonist which enhances protein synthesis and inhibits protein
degradation. When zilpaterol is given to animals, the net result is an increase skeletal muscle cross-sectional
area.
Pharmacokinetics
Zilpaterol was rapidly and completely absorbed, moderately metabolised and readily distributed throughout
the body following oral administration in laboratory species and humans. The main metabolites were N-
deisopropyl zilpaterol and hydroxy-zilpaterol, and an appropriate range of studies found no evidence of
bioaccumulative or persistent potential. The active chemical moiety is the parent compound, for which
pharmacological studies have demonstrated to be a tenfold more potent stimulator of the β2-receptor than its
major metabolite, N-deisopropyl zilpaterol, and for both compounds to have a higher affinity for the β2-
receptor relative to the β1-receptor. Zilpaterol appeared to be poorly absorbed dermally.
Acute toxicity (active constituent/product)
Zilpaterol was of moderate oral toxicity in mice (LD50 = 430–580 mg/kg bw) and low acute oral toxicity in rats
(LD50 = 890–1325 mg/kg bw). The intraperitoneal LD50 ranged from 155–170 mg/kg bw in mice to 225–280
mg/kg in rats. It was of low dermal (dermal LD50 > 2000 mg/kg bw, no deaths) and inhalational (LC50 > 5040
mg/m3, no deaths) toxicity in rats. No clinical signs, local irritation or deaths were seen in rats dermally
administered 2000 mg/kg zilpaterol.
Zilpaterol was slightly irritating to the eyes in rabbits, but not irritating to the skin in rabbits and non-
sensitising in guinea pigs.
Acute oral dosing studies in mice (Swiss OF1) and rats (Sprague Dawley SD) with the proposed product
Zilmax Medicated Premix demonstrated the formulation to be of low acute oral toxicity (LD50 >2000 mg/kg
bw, no deaths, for both studies).
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8 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Repeat-dose toxicity
Short-term and sub chronic toxicity was investigated in rats, dogs and microswine. Primary effects were
consistent with that expected for a beta II- adrenergic agonist, with observed changes in heart rate, heart
weight, peripheral vasodilation, blood pressure and haematology parameters.
In rats given zilpaterol hydrochloride orally via gavage at doses up to 50 mg/kg bw/d for 10 days or up to 100
mg/kg bw/d for 29 days, body weight gain was observed in treated animals. Changes in clinical chemistry
(reduced serum glucose and triglycerides) and haematological parameters (increased WBC and reduced
prothrombin time) were also noted, but there were no treatment related gross or microscopic lesions
identified at necropsy.
Rats were administered zilpaterol hydrochloride at doses up to 100 mg/kg bw/d for three months with a one
month recovery period for some animals. Food consumption and body weight gain were increased in all
treatment groups, although this was reversed during the recovery period. All treatment groups showed a
reduction in heart rate and increased cardiac conduction times. Serum urea and triglycerides, and heart
weights were increased in females at 1 mg/kg bw/d and in both sexes at 10 mg/kg bw/d. The change in heart
weights was still apparent at the end of the treatment period. A NOAEL was not established in this study.
In a further three-month oral gavage study, rats were administered zilpaterol hydrochloride at doses from
0.05 to 1 mg/kg bw/d. Food consumption and body weight gain were increased at 0.5 and 1.0 mg/kg bw/d. A
decrease in heart rate was noted in all treated female groups and males receiving 1 mg/kg bw/d. All treated
groups showed a higher mean PQ interval. Increased heart weights were observed in males and 1 mg/kg
bw/d and females at 0.5 and 1 mg/kg bw/d. Minimal to slight cardiomyopathy was seen in both treated and
control animals, however there was an increase in both incidence and severity in treated male groups. An
increased incidence of arteritis of large hepatic arteries was noted in 0.5 and 1 mg/kg bw/d males. A NOAEL
was not established in this study.
Two dogs administered 100 mg/kg bw/d zilpaterol hydrochloride in capsules for seven days demonstrated
significant treatment-related effects including frequent emesis, inactivity, apathy, lacrimation, vasodilatation
of ears and abdomen, and diarrhoea. Changes in haematological parameters (increased erythrocyte counts,
haematocrit and packed cell volume) and clinical chemistry (reduced total protein; increased cholesterol,
phospholipids, inorganic phosphorous, and liver enzymes (ALT, AST and ALP)) were noted. The livers of
treated animals were noted as being ‘putty-coloured’ with clear lobular structure. Histopathological
examination identified excess glycogen and lipids in the perilobular hepatocytes, and hypertrophy and
vacuolation of centrilobular hepatocytes.
When dogs were administered up to 50 mg/kg bw/d zilpaterol in capsules for 30 days, similar clinical signs
were observed as in the seven day study. In addition, peripheral vasodilatation was observed within 30
minutes of administration in all treated animals. Blood pressure was reduced and heart rate increased in all
treated animals. Gross necropsy findings were unremarkable.
In a 13-week oral gavage study in microswine administered zilpaterol hydrochloride at doses up to 10 mg/kg
bw/d, increased body weight gain was observed at the highest dose tested in males. In females, increased
erythrocytes, serum haemoglobin, haematocrit, potassium glucose, total protein and albumin levels were
observed. A NOAEL was established at 1 mg/kg bw/d.
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TOXICOLOGICAL ASSESSMENT 9
Chronic toxicity and carcinogenicity
Chronic dietary toxicity studies were conducted in female mice and in rats (both sexes).
In mice, no effects were seen at up to and including the highest dose tested of 0.25 mg/kg bw/d (0.250
mg/kg bw/d) in an 18-month oral gavage carcinogenicity study.
In a two-year carcinogenicity study in rats, changes in food consumption and decreased bodyweight gain
were seen at 0.25 mg/kg bw/d. In females, an increased incidence of leiomyoma (benign uterine smooth
muscle cell tumour) in the ovary suspensory ligament of 2/63 (three per cent, p
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10 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
in mice. It potentiated the neurobehavioural effect of 5-hydroxytryptophan in mice at 5 mg/kg bw and above,
and potentiated dexamphetamine-induced stereotypy in rats at 5 mg/kg bw.
Mode of action (toxicology)
Pharmacological effects of zilpaterol include agonist activity to beta II- adrenergic receptors. This is
associated with the cardiac effects seen in repeat dose studies.
Toxicity of metabolites and/or impurities
RU 62435 (deisopropyl zilpaterol) is the major metabolite of zilpaterol in rats and target species. It was found
to have low oral toxicity in mice (LD50 = 1030 mg/kg bw), was not mutagenic in bacteria at up to 5000
µg/plate or mouse lymphoma mutation assays at up to 800 µg/mL, and it did not induce unscheduled DNA
synthesis in rat hepatocytes in vitro or micronuclei in mouse bone marrow in vivo at oral doses of up to 400
mg/kg bw. The low acute oral toxicity is consistent the pharmacological agonist activity of deisopropyl
zilpaterol on beta II- adrenergic receptors being one-tenth of the parent compound.
Reports related to human toxicity
A double-blind randomised four way-crossover placebo controlled multicentre randomised study was
performed in 11 adult asthmatic out-patients at single oral doses of 0.05, 0.1 and 0.25 mg. Forced Expired
Volume (FEV1) was increased at 0.1 or 0.25 mg up to four hours after dosing and compared to the placebo
values, the actual-to-predicted FEV1 ratio was significantly higher. An increase in heart rate was recorded at
the dose of 0.25 mg up to six hours after dosing, with a slight, non-significant decrease in diastolic blood
pressure. A mild, short-lasting tremor occurred in eight patients at 0.25 mg and in two patients at 0.1 mg and
0.05 mg (equal to 0.76 μg/kg bw; none in placebo). The blood glucose level was increased one hour after the
0.25 mg dose. A NOAEL was not established.
3.2 Health-based guidance values and poisons scheduling
Poisons standard
In 1999, zilpaterol was listed In Schedule 4 of the Standard for the Uniform Scheduling of Medicines and
Poisons (SUSMP) without a concentration cut-off.
Health-based guidance values
Acceptable Daily Intake
The Acceptable Daily Intake (ADI) is that quantity of a chemical compound that can safely be consumed on a
daily basis for a lifetime.
An ADI of 0.04 μg/kg bw/d will be established for zilpaterol hydrochloride, based on the observation of
tremors at the lowest dose tested of 0.05 mg/person (equal to 0.76 μg/kg bw) in clinical examination of 11
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TOXICOLOGICAL ASSESSMENT 11
asthmatic volunteers, together with an uncertainty factor of 20, which is comprised of an intra-human
variability factor and a LOAEL to NOAEL extrapolation factor.
Acute Reference Dose
The Acute Reference Dose (ARfD) is the maximum quantity of a chemical that can safely be consumed over
a short period of time, usually in one meal or during one day.
As the proposed ADI is based on an acute pharmacological effect, establishment of an ARfD is appropriate.
The ARfD will be established equivalent to the ADI of 0.04 µg/kg bw, based on a LOAEL for tremors of 0.05
mg/person (equal to 0.76 μg/kg bw), and a 20-fold uncertainty factor based on the same rationale for the
proposed ADI.
3.3 Recommendations
The product, Zilmax Premedicated Premix, containing 48 g/kg zilpaterol hydrochloride, was found to have a
low oral toxicity in mice (LD50 > 2000 mg/kg bw in both sexes, no deaths) and rats (LD50 > 2000 mg/kg bw
in both sexes, no deaths).
The APVMA has considered the toxicological profile and likely exposure associated with the use of
formulated product Zilmax Medicated Premix and the active constituent zilpaterol hydrochloride. The APVMA
has concluded that the human health risk posed by the active and the product is acceptable according to the
criteria stipulated in Section 5A of the Agricultural and Veterinary Chemicals Code Act (1994).
There are no objections on human health grounds to the approval of the new active ingredient, zilpaterol
hydrochloride and registration of the product Zilmax Medicated Premix.
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12 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
4 RESIDUES ASSESSMENT
A similar residues dossier to that considered by Joint FAO/WHO Expert Committee on Food Additives
(JECFA)2 in 2013 (78th meeting) and 2015 (81st meeting) was submitted for evaluation.
4.1 Metabolism
Studies conducted in cattle, swine and rats demonstrated the metabolism of zilpaterol as qualitatively and
quantitatively comparable in these three species and is readily absorbed after oral administration. Zilpaterol
and its metabolites are readily eliminated, primarily in the urine (80 per cent in cattle, 85 per cent in swine
and 50 per cent in rats) with the remainder in the faeces. Unchanged zilpaterol was the main compound
excreted in the urine of these three species.
Radiolabelled residue depletion studies conducted in cattle after treatment at the recommended dose of 0.15
mg/kg bw/day demonstrated that a steady state is achieved by 12 days on treatment. Residues were
detected in liver and kidney until 96 hours post-dose in this study. No residues were detected in fat after 12
hours, and no residues were detected in muscle after 48 hours. At 12 hours post-dose, the radioactive
concentrations were observed in the following order:
liver=kidney>reticulum>omasum>abomasum>rumen >muscle >fat.
Zilpaterol represents a significant part of the extractable residue in liver, kidney and muscle. The ratio of
zilpaterol hydrochloride to extracted residue decreased with time for liver, kidney and muscle. Deisopropyl
zilpaterol was identified as a minor fraction of the extractable residue. The ratios of zilpaterol free base to
total pharmacologically active residue decreased from mean values of 94 per cent, 99 per cent and 92 per
cent at 12 hours to 74 per cent, 50 per cent, and 72 per cent at 96 hours for liver, kidney and muscle
respectively. Fat was not considered relevant for residue monitoring purposes due to the low potential for
residues in fat.
4.2 Analytical methods
A validated analytical procedure for the determination of zilpaterol in edible bovine tissues (liver, kidney,
muscle) is available. Samples of homogenized bovine tissue were fortified with a stable label internal
standard (d7-zilpaterol free base) and extracted with methanol. A sub-sample of the extract was purified by
cation exchange and then analysed by a validated liquid chromatography/mass spectrometry/mass
spectrometry (LC-MS/MS) method using electrospray ionization in the positive ion mode. Quantification was
performed using a solvent calibration curve with a range of 0.25 to 30 μg/kg tissue equivalents for all tissues.
The limit of quantitation (LOQ) was 0.250 μg/kg for liver, kidney and muscle, and the recovery of zilpaterol
was acceptable in these tissues.
Prior to the development of the aforementioned analytical method, a validated high performance liquid
chromatography fluorescence (HPLC/FL) methods was available. That method involves the extraction of
unchanged zilpaterol from liver, kidney and muscle homogenate with a basic mixture of acetonitrile and
2 apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=6191
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RESIDUES ASSESSMENT 13
methanol. The chemically stable fluorescent zilpaterol derivative is separated from other co-extractives and
non-fluorescent compounds by HPLC and detected with fluorescence detection. The LOQ was 3 µg/kg for
liver and 1 µg/kg for kidney and muscle.
4.3 Residue definition
Based on the available metabolism data, analytical methodology and residue depletion data, zilpaterol is
considered to be the appropriate marker residue for the proposed use of zilpaterol hydrochloride in beef
cattle.
4.4 Residues in food and animal feeds
The proposed use of Zilmax Medicated Premix in beef cattle involves its inclusion in manufactured feed at
8.3 g zilpaterol hydrochloride per tonne (8.3 mg/kg in the feed) on a 100 per cent dry matter basis to derive a
daily dose of 43–128 mg, depending on body weight. The proposed feeding duration is for the last 20 days in
the lead up to slaughter and the meat withholding period is ‘REMOVE ALL MEDICATED FEED four days
before slaughter for human consumption'.
The consideration of appropriate Maximum Residue Limits (MRLs) was based on the upper 95/95 tolerance
level associated with the concentration of the marker residue (zilpaterol). This was observed in a critical
residue depletion study which involved analysis with the LC/MS/MS analytical method with the LOQ of 0.25
μg/kg. Beef cattle were treated at 90 mg ai/head/day and animals (n=6) were sacrificed at 12, 24, 48, 72, 120
and 240 days after the last dose. The proposed directions for use specify that 87 mg zilpaterol
hydrochloride/animal should be applied for a 550 kg animal. Given the study animals weighed 503–525 kg at
study commencement and 541–614 kg at study completion, the 90 mg zilpaterol hydrochloride/animal
treatment is therefore equivalent to the proposed use.
The critical residues depletion study did not sample tissues at the proposed meat withholding period of four
days after the last dose, therefore the residue observations at three days after the last dose have been
considered. At three days after the last dose, residue observations were 1.2±0.34 µg/kg in liver, 1.0±0.02
µg/kg in kidney and 0.31±0.04 µg/kg in muscle. These levels had declined from a peak at the first sampling
interval of 12 hours of 36±12 µg/kg in liver, 28±0.89 µg/kg in kidney and 4.9±1.4 µg/kg in muscle. At the
sampling interval of 5 days, residues were 0.27±0.02 µg/kg in liver, 0.36±0.03 µg/kg in kidney and were
below LOQ (
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14 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
The restraints ‘DO NOT USE in cows which are producing or may in the future produce milk or milk products
for human consumption’ and ‘DO NOT USE in calves to be processed for veal’ are required as data
addressing the residue potential in milk or the tissues of pre-ruminant calves is not available.
The median and upper 95/95 tolerance limits for pharmacologically active residue as calculated by JECFA
for a 72 hour withdrawal period will be considered for the purposes of the dietary exposure calculations. The
median level of pharmacologically active residue after 72 hours of withdrawal were 2.4, 3.3 and 0.4 μg/kg in
liver, kidney, and muscle respectively. The upper 95/95 tolerance limits of pharmacologically active residue
after 72 hours of withdrawal were 6.2, 7.4 and 0.9 μg/kg in liver, kidney, and muscle respectively.
In the critical residue study, residue levels in liver and kidney at the 120 and 240 hour time-points were
similar indicating a plateau at low levels just above the LOQ of 0.25 µg/kg. In three other relevant residues
studies considered by JECFA at the 78th meeting in 2013, the LOQs were 3 µg/kg for liver and 1 µg/kg for
kidney and muscle and residues above those LOQ’s were not observed at or beyond 96 hours post-
treatment.
4.5 Estimated dietary intake
The ‘estimated daily intake’ for chronic dietary exposure based on the conservative JECFA food basket and
the median residue associated with the proposed use of zilpaterol in cattle after four days of withdrawal is
acceptable (
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RESIDUES ASSESSMENT 15
4.6 Recommended Maximum Residue Limits
The following amendments will be made to the APVMA MRL standard should the use pattern be approved
(Table 5).
Table 5: Amendments to the APVMA MRL Standard
Amendments to Table 1: MRLs for food commodities
Compound Food MRL (mg/kg)
ADD:
Zilpaterol
MF 0812 Cattle fat *0.00025
MO 1280 Cattle kidney 0.0033
MO 1281 Cattle liver 0.0035
Cattle muscle 0.0005
Amendments to Table 3: Residue definition
Compound Residue
ADD:
Zilpaterol Zilpaterol
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16 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
5 ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD
5.1 Commodities exported
Cattle meat and offal are considered to be major export commodities3. Residues of zilpaterol hydrochloride in
these commodities resulting from the use of Zilmax Medicated Premix have the potential to unduly prejudice
trade.
5.2 Destination and value of exports
The significant export markets for Australian beef meat and offals are listed in the APVMA Regulatory
Guidelines—Data Guidelines: Veterinary—Overseas trade (Part 5B). Codex, the European Union (EU),
Japan, the Republic of Korea, Taiwan and the United States are currently considered to be significant
markets for cattle.
In 2017–184, Australian beef and veal exports were valued at $7.96 billion with the major export destinations
being Japan, the United States, China and the Republic of Korea.
In 2018–195, the major export destinations of Australian beef offal include Indonesia, Japan, the Republic of
Korea, Hong Kong and South Africa.
5.3 Comparison of Australian MRLs with Codex and international MRLs
The Codex Alimentarius Commission (Codex) is responsible for establishing Codex Maximum Residue
Limits for pesticides and veterinary medicines. Some countries may accept Codex CXLs when importing
foods. Codex MRLs are not established for zilpaterol.
The Joint FAO/WHO Expert Committee on Food Additives (JECFA, 81st meeting, 2015) recommended
Codex MRLs for zilpaterol (free base) at 3.5 µg/kg for cattle liver, 0.5 µg/kg for cattle muscle and 3.3 µg/kg
for cattle kidney. The 23rd Codex Committee for Residues of Veterinary Drugs in Food (CCRVDF 236) in
October 2016 agreed to hold the proposed zilpaterol MRLs at Step 4, and therefore Codex MRLs were not
3 APVMA Regulatory Guidelines—Data Guidelines: Veterinary—Overseas trade (Part 5B)
4 ABARES Agricultural commodity statistics: agriculture.gov.au/abares/research-topics/agricultural-commodities/agricultural-commodities-trade-data#2018
5 MLA Australian offal Exports June 2019: mla.com.au/globalassets/mla-corporate/prices--markets/documents/os-markets/export-statistics/june-2019/1906---australian-offal-exports---global-summary.pdf
6 Report of CCRVDF 23: fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FMeetings%252FCX -730-23%252FReport%252FFinal%252FREP17_RVDFe.pdf
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ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD 17
established for zilpaterol. The EU, supported by some delegations, stated that they were opposed to the
advancement of zilpaterol in the Step procedure and to the establishment of Codex MRLs for zilpaterol. At
the next meeting (CCRVDF 247 in April 2018) it was emphasized that there were no public health or scientific
concerns regarding the proposed draft MRLs recommended by JECFA for zilpaterol. However the proposed
zilpaterol MRLs were again held at Step 4 as no consensus on the advancement of zilpaterol MRLs could be
reached due to the opposition from some delegations. Therefore Codex MRLs have not been established.
Zilmax is registered for use in beef cattle in various countries as outlined in Section 1.5 of this document with
a comparable use pattern to that proposed for Australia. Import tolerances have been established in Japan
and the applicant has noted that there is an ongoing procedure to establish import tolerance MRLs in
Taiwan. The EU and China have not established MRLs for zilpaterol.
The following relevant international MRLs have been established for zilpaterol (Table 6).
Table 6: Proposed Australian and current international MRLs for zilpaterol
Country MRLs/tolerances (µg/kg)
Liver Muscle Kidney Fat
Australia
(proposed)
3.5 0.5 3.3 *0.25
Brazil 35 4 55 -
Canada 5 2 5 -
Colombia 12 10 15 -
Costa Rica 12 10 15 -
Dominican
Republic
12 10 15 -
Guatemala 12 10 15 -
Honduras 12 10 15 -
Japan 10 10 10 10
Mexico 12 10 -
Nicaragua 12 10 15 -
Panama 12 10 15 -
Peru 12 10 15 -
7 Report of CCRVDF 24: fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FMeetings%252FCX -730-24%252FREPORT%252FREP18_RVDFe.pdf
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18 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Country MRLs/tolerances (µg/kg)
Liver Muscle Kidney Fat
Republic of
Korea
5 1 10 -
South Africa 12 10 15 -
USA 12 - - -
5.4 Potential risk to trade
Export of treated produce containing finite (measurable) residues of zilpaterol may pose a risk to Australian
trade in situations where (i) no residue tolerance (import tolerance) is established in the importing country or
(ii) where residues in Australian produce are likely to exceed a residue tolerance (import tolerance)
established in the importing country.
The zilpaterol MRLs established in Japan, the Republic of Korea and the United States are higher than that
proposed for Australia and the potential risk to trade to these markets is considered to be low and
acceptable. An Export Slaughter Interval equal to the proposed four day meat withholding period is
considered to be appropriate for these three major export markets.
MRLs are not established in the EU, China or Taiwan. Codex MRLs are not established which means that
many countries that may adopt Codex MRLs do not have appropriate MRLs. An Export Slaughter Interval for
these markets cannot be established as residues did not decline below the LOQ of 0.25 µg/kg in liver or
kidney at the last time point of 10 days. Residues above LOQ (0.25 µg/kg) were however not observed in
muscle or fat at five and 10 days after the last treatment. Therefore finite residues are not expected to occur
in meat following five days of withdrawal.
There is a risk to the international trade for cattle meat and offal associated with the proposed use with a four
day withdrawal time for the markets that have not established zilpaterol MRLs including the EU, China,
Taiwan, and countries that adopt Codex MRLs.
To assist in the mitigation of trade risk, the applicant has proposed a Zilpaterol Management Plan. This plan
is presented in Section 9.
The following Trade Advice statements are proposed for the product label
TRADE ADVICE: Exporters need to comply with the regulations/standards of importing countries with
regard to the use of animal health products in livestock. Producers are advised to contact their export
slaughter facility or Intervet Australia Pty Ltd for information before giving cattle feed to which this
product has been added.
EXPORT SLAUGHTER INTERVAL (ESI): DO NOT USE less than four days before slaughter for
export to markets for which zilpaterol MRLs are established. Before using this product confirm the
current export status for certain markets with Intervet Australia Pty Ltd on 1 800 033 461.
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ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD 19
For the APVMA to be satisfied that the registration of Zilmax Medicated Premix should not result in an undue
risk to the international trade of cattle meat and offal, it needs to be confident that the industry can manage
the potential risk to international trade.
Comment is therefore requested from industry stakeholders on the potential risk to trade associated with the
proposed use of Zilmax Medicated Premix. In particular industry feedback is being sought on aspects
relating to industry practices, proposed label statements and the proposed Zilpaterol Management Plan
(refer to Section 9) to prevent tissues from beef cattle exposed to zilpaterol being exported to countries that
do not currently have zilpaterol MRLs established such as China, the EU, Taiwan and countries that adopt
Codex MRLs.
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20 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
6 WORK HEALTH AND SAFETY ASSESSMENT
6.1 Health hazards
The formulation is supplied as a ready-to-use granular formulation with low-dust generation potential.
6.2 Occupational exposure
Exposure during use
Workers in livestock feed mills, livestock farmers and their employees will be the main users of the product.
Workers will be exposed to the product predominately by inhalation and eye contact during the preparation
of stock feed.
Exposure scenarios include: opening bags, weighing portions, mixing into carrier feed, storing treated carrier
feed, transferring treated carrier feed into feedlot pens, cleaning around feeding areas and disposing of
containers. Of these activities, mixing the product into carrier feed incurs the highest potential exposures to
zilpaterol.
Based on information indicating that workers may spend up to two hours per day preparing the premix and
feed mixture together with feedlot maintenance, the risk associated with inhalation exposure to zilpaterol was
considered acceptable (margin of exposure (MOE) >20) at both the 50th and 95th exposure percentile.
Exposure during re-entry or rehandling
The risk associated with re-entry/re-handling are considered minimal. Considering the limited re-handling of
treated feed, the toxicity profile of the active and product, and the concentration of active in the final feed, a
re-entry or re-handling statement is not required.
6.3 Public exposure
As Zilmax Medicated Premix is intended for commercial farming of beef cattle, and is not intended for
domestic use, the public are unlikely to use the product. The risk to the public from accidental exposure is
likely to be minimal. The most likely route of public exposure is through consumption of zilpaterol residues in
food derived from treated livestock.
6.4 Recommendations
The following first aid instructions, safety directions and precautionary (warning) statements are
recommended for the product label.
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WORK HEALTH AND SAFETY ASSESSMENT 21
First aid instructions
If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131 126; New Zealand
0800 764 766.
Safety directions
Harmful if swallowed. Harmful if inhaled especially the dust. May irritate the eye. Do not touch or rub eyes,
nose or mouth with hand when handling granules. When using the product wear goggles and a disposable
dust mask. Wash hands after use.
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22 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
7 ENVIRONMENTAL ASSESSMENT
The environmental assessment applied the standard VICH GL6 guidance for a Phase 1 assessment which
considers the primary route of entry of the active constituent into the environment is through excretion by
treated cattle.
7.1 Fate and behaviour in the environment
Soil
On the basis of metabolism and excretion data, it was assumed a total dose of 95 per cent was eliminated
(86 per cent in urine and 8.7 per cent in faeces), consisting mainly of zilpaterol as free base and numerous
metabolites. Approximately 13 per cent of the administered dose was deisopropyl zilpaterol which retains the
imidazole ring and is expected to exhibit similar activity.
Based on metabolism and excretion data and the worst-case parameters, a soil concentration of 81 µg ac/kg
was predicted. The predicted soil concentration was lower than the VICH Phase 1 trigger value of 100 µg/kg
soil. VICH guidance indicates that the trigger value of 100 µg/kg soil is considered to be below the levels
shown to have ecologically relevant effects for veterinary medicine products in general. Therefore,
environmental risks of the proposed use Zilmax Medicated Premix were determined to be acceptable.
7.2 Recommendations
In considering the environmental safety of the use of Zilmax Medicated Premix, the APVMA had regard to
the toxicity of the active constituent and its residues, including metabolites and degradation products, in
relation to relevant organisms and ecosystems. Based on the outcome of the risk assessment, the APVMA
proposes to be satisfied under s 14 of the Agricultural and Veterinary Chemicals Code Act 1994 that the use
of the product meets the safety and labelling criteria.
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EFFICACY AND SAFETY ASSESSMENT 23
8 EFFICACY AND SAFETY ASSESSMENT
8.1 Proposed product use pattern
Zilpaterol hydrochloride is a new β-agonist to the Australia market and is currently not approved for use as a
veterinary chemical product. The product, Zilmax Medicated Premix, contains 48 g/kg zilpaterol
hydrochloride as the active ingredient. Beta II- adrenergic agonists enhance animal growth by binding on to
beta II- adrenergic receptors on skeletal muscle cell and adipocytes. This binding modifies biochemical
processes of tissue growth by increasing lipolysis, decreasing lipogenesis, decreasing protein degradation,
and increasing protein synthesis.
The proposed claims are for increased carcass leanness, increased dressing percent, improved rate of body
weight gain and improved feed efficiency in cattle fed in confinement for slaughter during the last 20 days on
feed.
Zilmax Medicated Premix will be administered at 8.3 g zilpaterol hydrochloride per ton of feed to provide
between 43 mg to 128 mg zilpaterol hydrochloride per head per day on a 100 per cent dry matter basis. The
product is prohibited from administration to breeding cattle, horses or other equines.
8.2 Efficacy and target animal safety
Efficacy
The efficacy data provided included results from dose determination, dose confirmation and field studies.
The trial designs, treatment group sizes, ages and types of animals used, trial conditions, administration of
the test product, sample collection and analysis of data were generally appropriate for establishing efficacy
of the test product for the proposed use in cattle.
13 dose determination and confirmation studies were conducted on Charolais, Normandy, Sussex, Sussex X
Hereford, Bonsmara, and Angus cattle in France, Mexico and South Africa with dosing periods ranging from
15 to 118 days. The dose determination studies results supported the selection of an appropriate dose level
of 8.3 grams zilpaterol hydrochloride/tonne on a 100 per cent dry matter basis. The dose confirmation
studies demonstrated efficacy at approximately 1X and 2X the proposed use dose with dosing periods
ranging from 15 days to 118 days.
In five field studies conducted in USA and Canada on Angus, Angus cross, Red Angus, Red Angus cross,
Hereford, Hereford cross, Charolais, or Limousin cattle administered at the proposed dose for 20 to 40 days,
the product was effective in increasing carcass leanness, dressing percent, rate of body weight gain and
feed efficiency in cattle fed in confinement for slaughter. No Australian studies were conducted based on an
argument of strong similarities between cattle production in USA and Australian feedlots, cattle breeds,
feedlot management systems, nutrition and carcass characteristics.
No adverse effects were observed in any of the dose determination, dose confirmation and field studies.
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24 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Claims for the increasing weight gain, improved feed efficiency and increased carcass leanness in cattle fed
in confinement for slaughter during the last 20 days on feed, when the product is used at the proposed dose
rate of 8.3 grams Zilpaterol hydrochloride/tonne on a 100 per cent dry matter basis are supported.
Animal safety
In one target animal safety study in cross-bred fattening beef cattle, administered doses of 1X and 10X the
average recommended dose of 68 mg zilpaterol hydrochloride/day/head of the test product for 28 days (ad
lib feed intake) resulted in reduced feed intake resulting in mean dose levels of 44 mg/day (0.64X) and 302
mg/day (4X), respectively. Clinical signs included increased heart rates at the 10X dose. There were no
toxicological changes associated with the test product in any of the clinical parameters measured in terms of
clinical biochemistry, haematology and urinalysis, and gross and histopathology.
In a second target animal safety study in cross-bred fattening beef cattle, administered doses of 1X, 1.5X
and 10X the average recommended dose of 68 mg zilpaterol hydrochloride/day/head of the test product for
at least 40 days (ad lib feed intake) resulted in reduced feed intake resulting in mean dose levels 94 mg/day
(1.4X) and 520 mg/day (8X). There were no toxicological changes associated with the test product in any of
the clinical parameters measured in terms of clinical biochemistry, haematology and urinalysis.
In three target animal safety studies in steers, bullocks or Normandy heifers, administered doses of 1X and
2X the maximum recommended dose of 68 mg zilpaterol hydrochloride/day of the test product for 50 or 61
days (ad lib feed intake) resulted in increased heart rates.
Based on the evidence and literature provided by the applicant for registration as a new veterinary product,
the contraindications, side effects and other label statements proposed relating to target animal safety are
considered appropriate.
Contraindications
1. Not for use in cattle intended for breeding.
2. Horses and other equines must NOT be allowed access to feeds containing zilpaterol.
Side effects
Animals receiving Zilmax may exhibit an increased respiratory rate as well as elevated levels of creatine
phosphokinase (CPK) and creatinine.
Dosage and administration label statements
3. Do not feed undiluted.
4. Zilmax must be thoroughly mixed into feeds before use.
8.3 Recommendations
The APVMA has evaluated the efficacy and target animal safety data of the proposed product Zilmax Medicated
Premix, and found it to be acceptable. Based on a review of the data submitted, Zilmax Medicated Premix would
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EFFICACY AND SAFETY ASSESSMENT 25
be effective and would not be likely to have an unintended effect that is harmful to the target species when used as
directed.
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26 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
9 PROPOSED ZILPATEROL TRADE MANAGEMENT PLAN
The applicant has proposed the following Zilpaterol Management Plan to assist in the management of trade
risk:
9.1 Zilpaterol Management Plan
To manage the use of zilpaterol efficiently without posing undue risk to efficacy, safety, residue, trade and
environment, working effectively and collaboratively with existing industry systems will be important. These
systems include:
feedlots: National Feedlot Accreditation Scheme (NFAS)
processing plants: approved arrangements
property and livestock identification: National Livestock Identification Scheme (NLIS)
livestock movement advice: National Vendor Declaration (NVD) and NFAS delivery dockets.
It is proposed that the registered product label would include the following supply for use requirement:
‘Restraints: USE ONLY by authorised NFAS accredited feedlots.’
This restraint restricts the use of zilpaterol to NFAS accredited and authorised feedlots.
Feedlots
The National Feedlot Accreditation Scheme has agreed to develop a β-agonist management plan and
individual NFAS Accredited Feedlots will be required to develop feedlot specific QA policies and procedures
to ensure the correct use of zilpaterol. Individual feedlot QA policies and procedures will be audited by NFAS
prior to them gaining access to zilpaterol through accredited veterinarians. Feedlots will then continue to be
audited by NFAS to maintain zilpaterol approved use status.
Feedlots will adopt procedures to ensure full traceability of all animals through the NLIS and link individual
animal identification to the central NLIS database.
Quality processes and procedures will be adopted for all identified ‘Critical Control Points’ including but not
limited to:
storage and handling infrastructure
product purchase and receival
ration formulation
terminal drafting
pen identification and feed bunk isolation
feed batching
feed delivery
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PROPOSED ZILPATEROL TRADE MANAGEMENT PLAN 27
feed truck sanitisation
withholding periods
movements out of pens being fed zilpaterol
responses to accidental (known or possible) zilpaterol consumption
dispatch for slaughter
feed testing
record keeping.
Systems will be adopted to ensure that individual animals, from which meat and offal may be destined for
zilpaterol sensitive markets, do not have access to rations treated with zilpaterol.
Systems will be put in place to ensure that zilpaterol concentrate is stored securely, and that legislative
withholding periods and export slaughter intervals have been complied with prior to dispatch for slaughter.
Systems will be put in place to ensure that the supply and use of zilpaterol is controlled and recorded for audit.
The records will include, but not limited to:
the receipt and storage of each delivery of zilpaterol
feed ration formulation
feed ration mixing instructions
each batch of zilpaterol ration prepared (batch record)
each load of zilpaterol ration delivered to pens
feed truck cleaning validation and record
daily reconciliation of zilpaterol use
waste and disposal
compliance of withholding periods and export slaughter intervals
ration sampling program and testing results
action taken in the event of suspected accidental consumption of zilpaterol rations
written procedures for labelling to indicate status of containers, bunks, pens, trucks, rations, roughage
bays that may come into contact with zilpaterol.
Systems will be put in place to manage the risk of cross-contamination and actions to be taken in the event of
accidental access to zilpaterol treated feed.
There will be dedicated and physically identified pens for zilpaterol treated cattle.
Any cattle involved in accidental access to zilpaterol ration will be allocated to zilpaterol pens with a newly
assigned ‘beta-agonist-fed’ status on the NLIS database.
Frequent and regular sampling and testing to monitor the zilpaterol levels in treated feeds and confirm the
zilpaterol-free status of non-treated feeds.
Staff are properly trained before handling Zilpaterol concentrate.
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28 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
National livestock identification scheme and national vendor declaration
Each feedlot will be required to identify its Property Identification Code (PIC) on the NLIS database, prior to
the commencement of feeding zilpaterol.
Once the feedlot has determined the specific livestock to be fed zilpaterol, each animal’s NLIS device will be
allocated a device base status on the NLIS database indicating that it has been fed zilpaterol.
Should any livestock be transferred from a non-zilpaterol program to a zilpaterol program due to accidental
access to feed that contains zilpaterol, the NLIS tag of each such animal will be allocated a device base status
on the NLIS database indicating that the cattle have been fed zilpaterol.
All NLIS devices will be scanned at feedlot exit confirming that the devices are operational, ESI’s and WHP’s
have been complied with and that there are no zilpaterol fed cattle included in dispatches of cattle that are
declared as zilpaterol free.
NVD’s and NFAS delivery dockets for zilpaterol treated cattle need to be completed with Question 9 on the
NVD indicating that the cattle have been fed zilpaterol. Alternatively, these documents will be used to identify
cattle that have not been treated with zilpaterol.
Systems will be implemented to comply with the NLIS identification requirements for properties and individual
animals treated with zilpaterol and ensure that individual animals are segregated and identified at dispatch in
line with processor agreement.
Meat processing plants
Processing plants will follow existing Approved Arrangements procedures that are in place to protect the
integrity of products going to sensitive markets using unique carcass destination and product code numbers.
Feedlots will follow documented segregation and identification procedures for zilpaterol treated livestock as
agreed with processor partners prior to dispatch.
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LABELLING REQUIREMENTS 29
10 LABELLING REQUIREMENTS
Company Name: INTERVET AUSTRALIA PTY LTD
Product Name: ZILMAX MEDICATED PREMIX
APVMA Approval No: 67405/55972
Date: 4 FEB 2020
Label Name: Zilmax Medicated Premix
Signal Headings: PRESCRIPTION ANIMAL REMEDY
KEEP OUT OF REACH OF CHILDREN
READ SAFETY DIRECTIONS BEFORE OPENING OR USING
FOR ANIMAL TREATMENT ONLY
Constituent
Statements:
Zilpaterol hydrochloride 48 g/kg.
Claims: The active ingredient is zilpaterol hydrochloride, a beta II adrenergic agonist for
increased carcass leanness, increased dressing percent, improved rate of body
weight gain and improved feed efficiency in cattle fed in confinement for slaughter
during the last 20 days on feed.
Net Contents: 10 kg
Directions for Use:
Restraints: USE ONLY by authorised NFAS accredited feedlots.
DO NOT USE in cows which are producing or may in the future produce milk that
may be used or processed for human consumption.
DO NOT USE in calves to be processed for veal.
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30 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
Contraindications: Not for use in cattle intended for breeding.
Horses and other equines must NOT be allowed access to feeds containing
zilpaterol.
Precautions:
Side Effects: Animals receiving Zilmax may exhibit an increased respiratory rate as well as
elevated levels of creatine phosphokinase (CPK) and creatinine.
Dosage and
Administration:
FOR USE IN MANUFACTURED FEEDS ONLY.
DO NOT FEED UNDILUTED.
ZILMAX MUST BE THOROUGHLY MIXED INTO FEEDS BEFORE USE.
GENERAL MIXING INSTRUCTIONS:
IMPORTANT: Thoroughly mixing ZILMAX into an intermediate premix and mixing
the intermediate into the finished feed is recommended to ensure homogeneity. A
dilution of 1 part ZILMAX and 9 parts carrier is the suggested working premix.
Complete Feeds: Medicated feeds should be manufactured to 8.3 grams zilpaterol
hydrochloride/tonne on a 100% dry matter basis. ZILMAX and working premix
addition rates for complete feeds of varying dry matter are in the following table.
Complete Feed % Dry
Matter
Zilpaterol hydrochloride
Level (g/tonne)
Kg to Be Added Per Tonne of Feed
ZILMAX 1-9 Working Premix
60 5.0 0.104 1.04
70 5.8 0.121 1.21
80 6.7 0.140 1.40
90 7.5 0.156 1.56
100 8.3 0.173 1.73
Thoroughly mix both working premix and finished feed to ensure complete and
uniform distribution of the ZILMAX. Do not pellet medicated feeds containing
ZILMAX.
Feeding Directions: Complete feed for cattle fed in confinement for slaughter must
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LABELLING REQUIREMENTS 31
be fed continuously at a rate of 8.3 g zilpaterol hydrochloride/tonne on a 100% dry
matter basis for a period of 20 consecutive days at the end of the feeding period.
The recommended inclusion rate in complete feed for cattle fed in confinement is
8.3 g zilpaterol hydrochloride per tonne (8.3 ppm) on a 100% dry matter basis. The
amount of zilpaterol hydrochloride consumed daily by cattle fed in confinement for
slaughter will depend upon the consumption rate of the medicated feed. Zilpaterol
hydrochloride consumption will range between 43 and 128 mg per head per day
based on the consumption rates in the following table.
Cattle Weight (kg)
Average Feed Consumption1/Head/Day
100% Dry Matter (kg)
Zilpaterol hydrochloride Consumed Daily by each
Animal (mg)
350 5.25 43.58
400 6.40 53.12
450 7.65 63.50
500 9.00 74.70
550 10.45 86.74
600 12.00 99.60
650 13.65 113.30
700 15.50 128.65
1. Assumes ad libitum intake.
Liquid Feeds: ZILMAX may be added to Liquid feeds intended for addition to dry
feeds for cattle in confinement.
Liquid feeds should be in a pH range of 3.8 to 7.5.
Liquid feeds should be recirculated or agitated daily and prior to use for 10 to 20
minutes.
Liquid feeds can be manufactured containing 83 to 830 g zilpaterol
hydrochloride/tonne.
Before feeding, the medicated Liquid feed must be thoroughly mixed with other
feed materials to make a complete feed. Examples of addition rates to complete
feeds are shown in the following table.
Zilpaterol
hydrochloride in
Liquid Feed (g/tonne)
Addition Rate of Liquid
Feed to Complete Feed,
100% Dry Matter
(kg/tonne)
Zilpaterol hydrochloride in
Final Complete Feed,
100% Dry Matter
(g/tonne)
83 100 8.3
415 20 8.3
830 10 8.3
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32 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
General Directions:
Carcass Effects Effect of Zilpaterola
Dressing Percentage, % ↑
Hot Carcass Weight, kg ↑
Ribeye Area, sq.cm. ↑
Yield Grade ↓b
12th Rib Fat Thickness, cm NC
Marbling Score NC
Carcass Colour Score ↑c
Carcass Percent Protein, % ↑
a. The effect of zilpaterol on parameters listed in this table is supported by data generated at the dose tested in the clinical efficacy trials. NC = No Change, ↑ = increased, ↓ = decreased.
b. Reduction indicates an improvement in Yield Grade.
c. Increase indicates an improvement in Colour Score.
Withholding Periods: MEAT: REMOVE ALL MEDICATED FEED 4 days before slaughter for human
consumption
MILK: DO NOT USE in cows which are producing or may in the future produce milk
that may be used or processed for human consumption.
DO NOT USE in calves to be processed for veal
Trade Advice: Exporters need to comply with the regulations/standards of importing countries with
regard to the use of animal health products in livestock. Producers are advised to
contact their export slaughter facility or Intervet Australia Pty Ltd for information
before giving cattle feed to which this product has been added.
EXPORT SLAUGHTER INTERVAL (ESI): DO NOT USE less than 4 days before
slaughter for export to markets for which zilpaterol MRLs are established. Before
using this product confirm the current export status for certain markets with the
Intervet Australia Pty Ltd on 1 800 033 461.
Safety Directions: Harmful if swallowed. Harmful if inhaled especially the dust. May irritate the eyes.
Do not touch or rub eyes, nose or mouth with hand when handling granules. When
using the product wear goggles and a disposable dust mask. Wash hands after
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LABELLING REQUIREMENTS 33
use.
First Aid Instructions: If poisoning occurs, contact a doctor or Poisons Information Centre. Phone
Australia 131 126.
First Aid Warnings:
Additional User
Safety:
Environmental
Statements:
Use only in cattle feedlots that are compliant with the National Beef Cattle Feedlot
Environmental Code of Practice (2000) with respect to drainage management to
collect feedlot effluent.
Disposal: Shake container into medicated feed. Do not dispose of undiluted chemicals on-
site. Puncture bag and deliver to an approved waste management facility. If an
approved waste management facility is not available, bury the container 500 mm
below the surface in a disposal pit specifically marked and set up for this purpose
clear of waterways, vegetation and tree roots, in compliance with relevant local,
state or territory government regulations. Do not burn empty containers or product.
Storage: Store below 30oC (Room Temperature). Protect from light.
APVMA approval no: 67405/55972
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34 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
ABBREVIATIONS
ACCS/ACMS Advisory Committee for Chemicals Scheduling/Advisory Committee for Medicines
Scheduling
ac active constituent
ADI Acceptable Daily Intake (for humans)
ai active ingredient
ARfD Acute Reference Dose
bw bodyweight
d day
DAT Days After Treatment
DT50 Time taken for 50% of the concentration to dissipate
EbC50 concentration at which the biomass of 50% of the test population is impacted
EC50 concentration at which 50% of the test population are immobilised
EEC Estimated Environmental Concentration
ErC50 concentration at which the rate of growth of 50% of the test population is impacted
EI Export Interval
EGI Export Grazing Interval
ESI Export Slaughter Interval
EUP End Use Product
F0 original parent generation
g gram
GCP Good Clinical Practice
GLP Good Laboratory Practice
GVP Good Veterinary Practice
h hour
Hct Heamatocrit
Hb Haemoglobin
HPLC High Pressure Liquid Chromatography or High Performance Liquid Chromatography
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ABBREVIATIONS 35
in vitro outside the living body and in an artificial environment
in vivo inside the living body of a plant or animal
JECFA Joint FAO/WHO Expert Committee on Food Additives
kg kilogram
KOC Organic carbon partitioning coefficient
L Litre
LC50 concentration that kills 50% of the test population of organisms
LC-MS/MS Liquid chromatography/ mass spectrometry /mass spectrometry
LD50 dosage of chemical that kills 50% of the test population of organisms
LOD Limit of Detection—level at which residues can be detected
Log KOW Log to base 10 of octanol water partitioning co-efficient, synonym POW
LOQ Limit of Quantitation—level at which residues can be quantified
mg milligram
mL millilitre
MRL Maximum Residue Limit
MSDS Material Safety Data Sheet
NEDI National Estimated Daily Intake
NESTI National Estimated Short Term Intake
NOEC/NOEL No Observable Effect Concentration Level
NOAEL No Observed Adverse Effect Level
OC Organic Carbon
OM Organic Matter
po oral
ppb parts per billion
PPE Personal Protective Equipment
ppm parts per million
Q-value Quotient-value
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36 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
RBC Red Blood Cell Count
s second
SC Suspension Concentrate
SUSMP Standard for the Uniform Scheduling of Medicines and Poisons
TGA Therapeutic Goods Administration
TGAC Technical grade active constituent
µg microgram
vmd volume median diameter
WG Water Dispersible Granule
WHP Withholding Period
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GLOSSARY 37
GLOSSARY
Active constituent The substance that is primarily responsible for the effect produced by a chemical
product
Acute Having rapid onset and of short duration
Carcinogenicity The ability to cause cancer
Chronic Of long duration
Codex MRL Internationally published standard maximum residue limit
Desorption Removal of a material from or through a surface
Efficacy Production of the desired effect
Formulation A combination of both active and inactive constituents to form the end use product
Genotoxicity The ability to damage genetic material
Hydrophobic Repels water
Leaching Removal of a compound by use of a solvent
Metabolism The chemical processes that maintain living organisms
Photodegradation Breakdown of chemicals due to the action of light
Photolysis Breakdown of chemicals due to the action of light
Subcutaneous Under the skin
Toxicokinetics The study of the movement of toxins through the body
Toxicology The study of the nature and effects of poisons
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38 PUBLIC RELEASE SUMMARY ON ZILPATEROL HYDROCHLORIDE IN ZILMAX MEDICATED PREMIX
REFERENCES
APVMA 2015, Data Guidelines, Australian Pesticides and Veterinary Medicines Authority, Canberra,
available at apvma.gov.au/registrations-and-permits/data-guidelines.
CVMP (Committee for Medicinal Products for Veterinary Use), 2008, Revised guideline on environmental
impact assessments for veterinary medicinal products in support of the VICH Guidelines GL6 and GL38.
European Medicines Agency, Document Reference EMEA/CVMP/ERA/418282/2006-Rev.1.
VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary
Medicinal Products), 2000, Environmental impact assessment (EIAs) for veterinary medicinal products
(VMPs)–Phase 1, VICH GL6 (Ecotoxicity Phase 1).
https://apvma.gov.au/registrations-and-permits/data-guidelines
PrefaceAbout this document Making a submission Further information
1 Introduction1.1 Applicant 1.2 Purpose of application 1.3 Proposed claims and use pattern 1.4 Mode of action 1.5 Overseas registrations
2 Chemistry and manufacture2.1 Active constituent Table 1: Nomenclature and structural formula of the active constituent zilpaterol hydrochlorideTable 2: Key physicochemical properties of the active constituent zilpaterol hydrochloride2.2 Formulated product Table 3: Key aspects of the formulated product Zilmax Medicated PremixTable 4: Physicochemical properties of the product Zilmax Medicated Premix2.3 Recommendations
3 Toxicological assessment3.1 Evaluation of toxicology Chemical class and mode of activity Pharmacokinetics Acute toxicity (active constituent/product) Repeat-dose toxicity Chronic toxicity and carcinogenicity Reproductive and developmental toxicity Genotoxicity Neurotoxicity Mode of action (toxicology) Toxicity of metabolites and/or impurities Reports related to human toxicity
3.2 Health-based guidance values and poisons scheduling Poisons standard Health-based guidance values Acceptable Daily Intake Acute Reference Dose
3.3 Recommendations
4 Residues assessment4.1 Metabolism 4.2 Analytical methods 4.3 Residue definition 4.4 Residues in food and animal feeds 4.5 Estimated dietary intake 4.6 Recommended Maximum Residue Limits Table 5: Amendments to the APVMA MRL Standard
5 Assessmenet of overseas trade aspects of residues in food5.1 Commodities exported 5.2 Destination and value of exports 5.3 Comparison of Australian MRLs with Codex and international MRLs Table 6: Proposed Australian and current international MRLs for zilpaterol
5.4 Potential risk to trade
6 Work health and safety assessment6.1 Health hazards 6.2 Occupational exposure Exposure during use Exposure during re-entry or rehandling
6.3 Public exposure 6.4 Recommendations First aid instructions Safety directions
7 Environmental assessment7.1 Fate and behaviour in the environment Soil
7.2 Recommendations
8 Efficacy and safety assessment8.1 Proposed product use pattern 8.2 Efficacy and target animal safety Efficacy Animal safety Contraindications Side effects Dosage and administration label statements
8.3 Recommendations
9 Proposed zilpaterol trade management plan9.1 Zilpaterol Management Plan Feedlots National livestock identification scheme and national vendor declaration Meat processing plants
10 Labelling requirementsAbbreviationsGlossaryReferences